Myosin Regulatory light chain interacting protein (Mylip) is an ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth in neurons. The Mylip protein comprises a FERM homology domain at the N-terminus, and a RING zinc finger ubiquitin ligase domain at the C-terminus. While FERM-containing proteins are known to interact with the cytoplasmic regions of transmembrane proteins, Mylip is presently the only FERM-containing protein known to interact with the myosin regulatory light chain protein. Mylip is expressed ubiquitously in almost all human tissues.
Mylip has been shown to downregulate the LDL receptor by enhancing LDL receptor ubiquitination and leading to degradation of the LDL receptor (LDL-R). Overexpression of the Mylip protein in mice reduces levels of the LDL-R, decreases LDL uptake into cells and increases plasma cholesterol levels. Conversely, inhibition of Mylip expression in mice enhances LDL uptake into cells. Given the actions of Mylip on LDL-R expression, the protein is also referred to as ‘inducible degrador of the LDL-R’ (Idol).
Autosomal dominant hypercholesterolemias (ADHs) are monogenic diseases in which patients exhibit elevated total and LDL cholesterol levels, tendon xanthomas, and premature atherosclerosis (Rader, D. J., (2003) J. Clin. Invest. 111, 1795-1803). The pathogenesis of ADHs and a recessive form, autosomal recessive hypercholesterolemia (ARH) (Cohen, J. C., (2003) Curr. Opin. Lipidol. 14, 121-127), is due to defects in LDL uptake by the liver. ADH may be caused by LDLR mutations, which prevent LDL uptake, or by mutations in the protein on LDL, apolipoprotein B, which binds to the LDLR. ARH is caused by mutations in the ARH protein that are necessary for endocytosis of the LDLR-LDL complex via its interaction with clathrin. As Mylip/Idol plays a role in receptor-mediated LDL uptake it is likely that treatment strategies directed at Mylip/Idol would be beneficial in the above-described disorders.